Mechanism of Action of Strattera (Atomoxetine)
Strattera (atomoxetine) works primarily as a selective norepinephrine reuptake inhibitor that blocks the presynaptic norepinephrine transporter in the prefrontal cortex, increasing both norepinephrine and dopamine levels in this brain region. 1, 2
Primary Mechanism
Atomoxetine functions through:
- Selective inhibition of the presynaptic norepinephrine transporter 1
- High affinity and selectivity for norepinephrine transporters 3
- Minimal affinity for other neurotransmitter receptors 2
Unique Prefrontal Cortex Effects
In the prefrontal cortex specifically:
- Norepinephrine transporters also regulate dopamine reuptake due to scarcity of dopamine transporters in this region 2
- This results in increased levels of both norepinephrine and dopamine in prefrontal cortical synapses 2
- Preferentially binds to areas with high distribution of noradrenergic neurons, particularly the fronto-cortical subsystem 3
Pharmacokinetics
Key pharmacokinetic properties include:
- Rapid oral absorption with bioavailability of approximately 63% in extensive metabolizers and 94% in poor metabolizers 1
- Primarily metabolized through the CYP2D6 enzymatic pathway 1
- Half-life of about 5 hours in extensive metabolizers and 24 hours in poor metabolizers (approximately 7% of Caucasians and 2% of African Americans) 1
- Can be administered once daily or split into two evenly divided doses 3
- Food decreases the rate but not extent of absorption (37% lower Cmax when taken with food) 1
Clinical Distinction from Stimulants
Unlike stimulant medications for ADHD, atomoxetine:
- Is not classified as a stimulant 3
- Has negligible risk of abuse or misuse 3
- Is not a controlled substance in the US 3
- Is particularly useful for patients at risk of substance abuse or those who do not wish to take a controlled substance 3
Dosing Considerations
Standard dosing parameters:
- Usual starting dose: 40 mg daily 2
- Titration: Dose usually adjusted every 7-14 days to 60 then 80 mg/day 2
- Maximum recommended dose: 1.4 mg/kg/day or 100 mg/day, whichever is lower 2
Safety Considerations
Important monitoring parameters:
- May cause modest increases in heart rate and blood pressure 3
- Special warnings exist for suicidal ideation, particularly during the first few months of treatment 2
- Rare risk of serious liver injury has been reported in post-marketing data 3
Understanding atomoxetine's unique mechanism of action helps explain its efficacy in ADHD treatment while offering an important non-stimulant option for patients who cannot tolerate or should avoid stimulant medications.